Process for the preparation of esters by means of carbonylation of ethers

ABSTRACT

The invention relates to a process comprising the process steps of:
         a) initially charging an ether having from 3 to 30 carbon atoms;   b) adding a phosphine ligand and a compound comprising Pd, or adding a comprising Pd and a phosphine ligand;   c) feeding in CO;   d) heating the reaction mixture, with conversion of the ether; wherein the phosphine ligand is a compound of formula (I)       

     
       
         
         
             
             
         
       
         
         
           
             where 
             m and n are each independently 0 or 1; 
             R 1 , R 2 , R 3 , R 4  are each independently selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, —(C 3 -C 20 )-heteroaryl; 
             at least one of the R 1 , R 2 , R 3 , R 4  radicals is a —(C 3 -C 20 )-heteroaryl radical; and 
             R 1 , R 2 , R 3 , R 4 , if they are —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl or —(C 3 -C 20 )-heteroaryl, 
             may each independently be substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 1 -C 12 )-alkyl-(C 6 -C 20 )-aryl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —(C 6 -C 20 )-aryl, —(C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, —(C 6 -C 20 )-aryl-O—(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl, —(C 3 -C 20 )heteroaryl-(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl-O—(C 1 -C 12 )-alkyl, —COOH, —SO 3 H, —NH 2 , halogen; and wherein no alcohol is added to the reaction mixture.

The invention relates to a novel process for the preparation of estersby means of carbonylation of ethers.

The alkoxycarbonylation of ethylenically unsaturated compounds is aknown process for preparing esters. This process involves the reactionof ethylenically unsaturated compounds (olefins) with carbon monoxideand alcohols in the presence of a metal-ligand complex to give thecorresponding esters. Typically, the metal used is palladium. Thefollowing scheme shows the general reaction equation of analkoxycarbonylation:

A very good catalytic system for this process was developed by Lucitenow Mitsubishi Rayon and uses a ligand based on1,2-bis(di-tert-butylphosphinomethyl)benzene (DTBPMB) (W. Clegg, G. R.Eastham, M. R. J. Elsegood, R. P. Tooze, X. L. Wang, K. Whiston, Chem.Commun. 1999, 1877-1878).

Carrying out the alkoxycarbonylation from raw materials other thanethylenic unsaturated compounds is hitherto unknown. A problem addressedby the present invention is therefore that of providing a process forpreparing esters wherein raw materials other than ethylenic unsaturatedcompounds are used as a starting product. Of particular interest in thiscontext is the use of ethers as the starting product,

It has surprisingly emerged that this problem is solved by a processwherein ethers are reacted directly to esters with CO in the presence ofparticular benzene-based diphosphine ligands in which at least onephosphine group is substituted by a hetereoaryl radical, directly. Afeature of the process of the invention is that there is no need foralcohol to be added to the reaction. The invention, therefore, affordsan inexpensive and simple route to the preparation of esters, which,relative to the conventional alkoxycarbonylation, not only allows ethersto be used as a starting product but also makes it unnecessary foralcohols to be used as a further reactant.

The invention relates to a process comprising the process steps of:

-   -   a) initially charging an ether having from 3 to 30 carbon atoms;    -   b) adding a phosphine ligand and a compound comprising Pd, or        adding a complex comprising Pd and a phosphine ligand;    -   c) feeding in CO;    -   d) heating the reaction mixture, with conversion of the ether to        an ester; wherein the phosphine ligand is a compound of formula        (I)

where

m and n are each independently 0 or 1;

R¹, R², R³, R⁴ are each independently selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl,—(C₃-C₂₀)-heteroaryl;

at least one of the R¹, R², R³, R⁴ radicals is a —(C₃-C₂₀)-heteroarylradical;

and

R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl or —(C₃-C₂₀)-heteroaryl,

may each independently be substituted by one or more substituentsselected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —COO—(C₁-C₁₂)-alkyl,—COO—(C₃-C₁₂)-cycloalkyl, —CONH—(C₁-C₁₂)-alkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —CO—(C₁-C₁₂)-alkyl, —CO—(C₃-C₁₂)-cycloalkyl,—N—[(C₁-C₁₂)-alkyl]₂, —(C₆-C₂₀)-aryl, —(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl,—(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COOH, —SO₃H, —NH₂, halogen; andwherein no alcohol is added to the reaction mixture.

In this process, process steps a), b) and c) can be effected in anydesired sequence. Typically, however, the addition of CO is effectedafter the co-reactants have been initially charged in steps a) and b).Steps c) and d) can be effected simultaneously or successively. Inaddition, CO can also be fed in in two or more steps, in such a waythat, for example, a portion of the CO is first fed in, then the mixtureis heated, and then a further portion of CO is fed in.

The process of the invention envisages no additional alcohol being addedto the reaction mixture. This therefore distinguishes the process of theinvention critically from the alkoxycarbonylation processes known in theprior art, which use an alcohol as a reactant. In the context of theinvention, however, the formation of an alcohol as a by-product orintermediate in the course of the reaction is not ruled out.

In one embodiment, the phosphine ligands according to the invention arecompounds of one of the formulae (II) and (III)

In these formulae, the R¹, R², R³, R⁴ radicals are each as definedabove.

In one particularly preferred embodiment, the phosphine ligand of theinvention is a compound of the formula (II) wherein the radicals R¹, R²,R³ and R⁴ are as defined above.

The expression (C₁-C₁₂)-alkyl encompasses straight-chain and branchedalkyl groups having 1 to 12 carbon atoms. These are preferably(C₁-C₈)-alkyl groups, more preferably (C₁-C₆)-alkyl, most preferably(C₁-C₄)-alkyl.

Suitable (C₁-C₁₂)-alkyl groups are especially methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl,2-heptyl, 3-heptyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl,2-propylheptyl, nonyl, decyl.

The elucidations relating to the expression (C₁-C₁₂)-alkyl also applyparticularly to the alkyl groups in —O—(C₁-C₁₂)-alkyl,—S—(C₁-C₁₂)-alkyl, —COO—(C₁-C₁₂)-alkyl, —CONH—(C₁-C₁₂)-alkyl,—CO—(C₁-C₁₂)-alkyl and —N—[(C₁-C₁₂)-alkyl]₂.

The expression (C₃-C₁₂)-cycloalkyl encompasses mono-, bi- or tricyclichydrocarbyl groups having 3 to 12 carbon atoms. Preferably, these groupsare (C₅-C₁₂)-cycloalkyl,

The (C₃-C₁₂)-cycloalkyl groups have preferably 3 to 8, more preferably 5or 6, ring atoms.

Suitable (C₃-C₁₂)-cycloalkyl groups are especially cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclododecyl, cyclopentadecyl, norbornyl, adamantyl.

The elucidations relating to the expression (C₃-C₁₂)-cycloalkyl alsoapply particularly to the cycloalkyl groups in —O—(C₃-C₁₂)-cycloalkyl,—S—(C₃-C₁₂)-cycloalkyl, —COO—(C₃-C₁₂)-cycloalkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —COO—(C₃-C₁₂)-cycloalkyl.

The expression (C₃-C₁₂)-heterocycloalkyl encompasses nonaromatic,saturated or partly unsaturated cycloaliphatic groups having 3 to 12carbon atoms, where one or more of the ring carbon atoms are replaced byheteroatoms. The (C₃-C₁₂)-heterocycloalkyl groups have preferably 3 to8, more preferably 5 or 6, ring atoms and are optionally substituted byaliphatic side chains. In the heterocycloalkyl groups, as opposed to thecycloalkyl groups, one or more of the ring carbon atoms are replaced byheteroatoms or heteroatom-containing groups. The heteroatoms or theheteroatom-containing groups are preferably selected from O, S, N,N(═O), C(═O), S(═O). A (C₃-C₁₂)-heterocycloalkyl group in the context ofthis invention is thus also ethylene oxide.

Suitable (C₃-C₁₂)-heterocycloalkyl groups are especiallytetrahydrothiophenyl, tetrahydrofuryl, tetrahydropyranyl and dioxanyl.

The expression (C₆-C₂₀)-aryl encompasses mono- or polycyclic aromatichydrocarbyl radicals having 6 to 20 carbon atoms. These are preferably(C₆-C₁₄)-aryl, more preferably (C₆-C₁₀)-aryl.

Suitable (C₆-C₂₀)-aryl groups are especially phenyl, naphthyl, indenyl,fluorenyl, anthracenyl, phenanthrenyl, naphthacenyl, chrysenyl, pyrenyl,coronenyl. Preferred (C₆-C₂₀)aryl groups are phenyl, naphthyl andanthracenyl.

The expression (C₃-C₂₀)-heteroaryl encompasses mono- or polycyclicaromatic hydrocarbyl radicals having 3 to 20 carbon atoms, where one ormore of the carbon atoms are replaced by heteroatoms. Preferredheteroatoms are N, O and S. The (C₃-C₂₀)-heteroaryl groups have 3 to 20,preferably 6 to 14 and more preferably 6 to 10 ring atoms.

Suitable (C₃-C₂₀)-heteroaryl groups are especially furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, furazanyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl,pyrazinyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, quinolyl,isoquinolyl.

The expression halogen especially encompasses fluorine, chlorine,bromine and iodine. Particular preference is given to fluorine andchlorine.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,—(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl, —(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COOH, —SO₃H, —NH₂, halogen.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,—(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl, —(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyland —(C₃-C₂₀)-heteroaryl.

In one embodiment, the R¹, R², R³, R⁴ radicals are unsubstituted if theyare —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, or—(C₃-C₁₂)-heterocycloalkyl, and may be substituted as described if theyare —(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl.

In one embodiment, the R¹, R², R³, R⁴ radicals are unsubstituted if theyare —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl.

In one embodiment, R¹, R², R³, R⁴ are each independently selected from—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl;

where at least one of the R¹, R², R³, R⁴ radicals is a—(C₃-C₂₀)-heteroaryl radical;

and R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl or—(C₃-C₂₀)-heteroaryl, may each independently be substituted by one ormore of the above-described substituents.

In one embodiment, at least two of the R¹, R², R³, R⁴ radicals are a—(C₃-C₂₀)-heteroaryl radical.

In one embodiment, the R¹ and R³ radicals are each a—(C₃-C₂₀)-heteroaryl radical and may each independently be substitutedby one or more of the substituents described above. Preferably, R² andR⁴ are independently selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl, morepreferably from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,most preferably from —(C₁-C₁₂)-alkyl. R² and R⁴ may independently besubstituted by one or more of the above-described substituents.

In one embodiment, the R¹, R², R³ and R⁴ radicals are a—(C₅-C₂₀)-heteroaryl radical and may each independently be substitutedby one or more of the substituents described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are each independently selected from heteroarylradicals having five to ten ring atoms, preferably five or six ringatoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, a heteroaryl radical having five ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are each independently selected from heteroarylradicals having six to ten ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are a heteroaryl radical having six ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,furazanyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,benzofuranyl, indolyl, isoindolyl, benzimidazolyl, quinolyl,isoquinolyl, where the heteroaryl radicals mentioned may be substitutedas described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from furyl, thienyl, pyrrolyl,imidazolyl, pyridyl, pyrimidyl, indolyl, where the heteroaryl radicalsmentioned may be substituted as described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from 2-furyl, 2-thienyl, 2-pyrrolyl,2-imidazolyl, 2-pyridyl, 2-pyrimidyl, 2-indolyl, where the heteroarylradicals mentioned may be substituted as described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from 2-furyl, 2-thienyl,N-methyl-2-pyrrolyl, N-phenyl-2-pyrrolyl,N-(2-methoxyphenyl)-2-pyrrolyl, 2-pyrrolyl, N-methyl-2-imidazolyl,2-imidazolyl, 2-pyridyl, 2-pyrimidyl, N-phenyl-2-indolyl, 2-indolyl,where the heteroaryl radicals mentioned have no further substitution.

More preferably, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are pyridyl, especially 2-pyridyl.

In one embodiment, R¹ and R³ are a pyridyl radical, preferably2-pyridyl, and R² and R⁴ are —(C₁-C₁₂)-alkyl, where R¹, R², R³ and R⁴may each be substituted as described above.

In one embodiment, the ligands are a compound of the formula (1):

The ethers used as a reactant in step a) in the process of the inventioncomprise 3 to 30 carbon atoms, preferably 3 to 22 carbon atoms, morepreferably 3 to 12 carbon atoms. The ethers may derive from primary,secondary or tertiary alcohols. The ethers may also be cyclic ethers.

In one embodiment the ethers are acyclic and derive from a primary,secondary or tertiary alcohol. Preferably the ethers derive from asecondary or tertiary alcohol. Particularly preferred ethers are thosederiving from a tertiary alcohol.

In one embodiment, the ether is a compound of the formula (IV)

where R⁵ is selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₆-C₂₀)-aryl;

R⁶ and R⁷ each independently are selected from —H, —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl;

and R⁸ is selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₆-C₂₀)-aryl.

In one preferred embodiment, R⁵ and R⁸ are each —(C₁-C₁₂)-alkyl.Preferably R⁵ and R⁸ are each selected from methyl, ethyl, n-propyl,2-propyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl,2-methylbut-2-yl, 2,2-dimethylpropyl. With particular preference R⁵ andR⁸ are each selected from methyl and ethyl. Most preferably R⁵ and R⁸are each methyl.

In one preferred embodiment R⁶ and R⁷ are each independently selectedfrom —H, —(C₁-C₁₂)-alkyl and —(C₆-C₂₀)-aryl. Preferably R⁶ and R⁷ areeach independently selected from —H, methyl, ethyl, n-propyl, 2-propyl,n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,2,2-dimethylpropyl and phenyl. With particular preference R⁶ and R⁷ areeach independently selected from —H, methyl, ethyl, n-propyl, 2-propyl,n-butyl, 2-butyl, sec-butyl, tert-butyl and phenyl.

Preferably not more than one of the radicals R⁶ and R⁷ is —H.

In one alternative embodiment R⁶ and R⁷ are each independently selectedfrom (C₁-C₁₂)alkyl and —(C₆-C₂₀)-aryl. In this case preferably R⁶ and R⁷are each independently selected from methyl, ethyl, n-propyl, 2-propyl,n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,2,2-dimethylpropyl and phenyl. Particularly preferably R⁶ and R⁷ in thiscase are each independently selected from methyl, ethyl, n-propyl,2-propyl, n-butyl, 2-butyl, sec-butyl, tert-butyl and phenyl. In thisembodiment, in particular, R⁵ may be methyl, with R⁶ and R⁷ eachselected independently from methyl, tert-butyl and phenyl.

In one preferred embodiment the ether is methyl tert-butyl ether.

The alkoxycarbonylation according to the invention is catalysed by a Pdcomplex. The Pd complex may either be added in process step b) as apreformed complex comprising Pd and the phosphine ligands or be formedin situ from a compound comprising Pd and the free phosphine ligand. Inthis context, the compound comprising Pd is also referred to as catalystprecursor.

The preformed complexes may also comprise further ligands whichcoordinate to the metal atom. These are, for example, ethylenicallyunsaturated compounds or anions. Suitable additional ligands are, forexample, styrene, acetate anions, maleimides (e.g. N-methylmaleimide),1,4-naphthoquinone, trifluoroacetate anions or chloride anions.

In the case that the catalyst is formed in situ, the ligand can be addedin excess, such that the unbound ligand is also present in the reactionmixture.

In the case of the complex which is added right at the start as well, itis also possible to add further ligand, such that unbound ligand is alsopresent in the reaction mixture.

In one variant, the compound comprising Pd is selected from palladiumchloride (P palladium(II) acetylacetonate [Pd(acac)₂], palladium(II)acetate [Pd(OAc)₂], dichloro(1,5-cyclooctadiene)palladium(II)[Pd(cod)₂Cl₂], bis(dibenzylideneacetone)palladium [Pd(dba)₂],bis(acetonitrile)dichloropalladium(II) [Pd(CH₃CN)₂Cl₂],palladium(cinnamyl) dichloride [Pd(cinnamyl)Cl₂].

Preferably, the compound comprising Pd is PdCl₂, Pd(acac)₂ or Pd(OAc)₂.Pd(acac)₂ is particularly suitable.

In one variant of the process, a solvent is added to the reactionmixture. In this case, the solvent may be selected, for example, from:toluene, xylene, tetrahydrofuran (THF) and methylene chloride (CH₂Cl₂).Preferably toluene is added to the reaction mixture as the solvent.

CO is fed in in step c) preferably at a partial CO pressure between 0.1and 10 MPa (1 to 100 bar), preferably between 1 and 8 MPa (10 to 80bar), more preferably between 2 and 4 MPa (20 to 40 bar).

The reaction mixture is heated in step d) of the process according tothe invention preferably to a temperature between 10° C. and 180° C.,preferably between 20 and 160° C., more preferably between 40 and 120°C., in order to convert the ether to an ester.

The mass ratio of Pd to the ether initially charged in step a) ispreferably between 0.001% and 0.5% by weight, preferably between 0.01%and 0.1% by weight, more preferably between 0.01% and 0.05% by weight.

The molar ratio of the phosphine ligand to Pd is preferably between0.1:1 and 400:1, preferably between 0.5:1 and 400:1, more preferablybetween 1:1 and 100:1, most preferably between 2:1 and 50:1.

Preferably, the process is conducted with addition of an acid. In onevariant, the process therefore additionally comprises step b′): addingan acid to the reaction mixture. This may preferably be a Brønsted orLewis acid.

Suitable Brønsted acids preferably have an acid strength of pK_(a)≦5,preferably an acid strength of pK_(a)≦3. The reported acid strengthpK_(a) is based on the pK_(a) determined under standard conditions (25°C., 1.01325 bar). In the case of a polyprotic acid, the acid strengthpK_(a) in the context of this invention relates to the pK_(a) of thefirst protolysis step.

Preferably, the acid is not a carboxylic acid.

Suitable Brønsted acids are, for example, perchloric acid, sulphuricacid, phosphoric acid, methylphosphonic acid and sulphonic acids.Preferably, the acid is sulphuric acid or a sulphonic acid. Suitablesulphonic acids are, for example, methanesulphonic acid,trifluoromethanesulphonic acid, tert-butanesulphonic acid,p-toluenesulphonic acid (PTSA), 2-hydroxypropane-2-sulphonic acid,2,4,6-trimethylbenzenesulphonic acid and dodecylsulphonic acid.Particularly preferred acids are sulphuric acid, methanesulphonic acid,trifluoromethanesulphonic acid and p-toluenesulphonic acid.

A Lewis acid used may, for example, be aluminium triflate.

In one embodiment, the amount of acid added in step b′) is 0.3 to 40 mol%, preferably 0.4 to 15 mol %, more preferably 0.5 to 5 mol %, mostpreferably 0.6 to 4 mol %, based on the molar amount of the ether usedin step a).

EXAMPLES

The examples which follow illustrate the invention.

General Procedures

All the preparations which follow were carried out under protective gasusing standard Schlenk techniques. The solvents were dried over suitabledesiccants before use (Purification of Laboratory Chemicals, W. L. F.Armarego (Author), Christina Chai (Author), Butterworth Heinemann(Elsevier), 6th edition, Oxford 2009).

Phosphorus trichloride (Aldrich) was distilled under argon before use.All preparative operations were effected in baked-out vessels. Theproducts were characterized by means of NMR spectroscopy. Chemicalshifts (δ) are reported in ppm. The ³¹P NMR signals were referenced asfollows: SR_(31P)=SR_(1H)*(BF_(31P)/BF_(1H))=SR_(1H)*0.4048. (Robin K.Harris, Edwin D. Becker, Sonia M. Cabral de Menezes, Robin Goodfellow,and Pierre Granger, Pure Appl. Chem., 2001, 73, 1795-1818; Robin K.Harris, Edwin D. Becker, Sonia M. Cabral de Menezes, Pierre Granger, RoyE. Hoffman and Kurt W. Zilm, Pure Appl. Chem., 2008, 80, 59-84).

The recording of nuclear resonance spectra was effected on Bruker Avance300 or Bruker Avance 400, gas chromatography analysis on Agilent GC7890A, elemental analysis on Leco TruSpec CHNS and Varian ICP-OES 715,and ESI-TOF mass spectrometry on Thermo Electron Finnigan MAT 95-XP andAgilent 6890 N/5973 instruments.

Preparation of chloro-2-pyridyl-tert-butylphosphine (Precursor A)

The Grignard for the synthesis of chloro-2-pyridyl-t-butylphosphine isprepared by the “Knochel method” with isopropylmagnesium chloride(Angew. Chem. 2004, 43, 2222-2226). The workup is effected according tothe method of Budzelaar (Organometallics 1990, 9, 1222-1227).

8.07 ml of a 1.3 M isopropylmagnesium chloride solution (Knochel'sreagent) are introduced into a 50 ml round-bottom flask with magneticstirrer and septum, and cooled to −15° C. Thereafter, 953.5 μl (10 mmol)of 2-bromopyridine are rapidly added dropwise. The solution immediatelyturns yellow. It is allowed to warm up to −10° C. The conversion of thereaction is determined as follows: about 100 μl solution are taken andintroduced into 1 ml of a saturated ammonium chloride solution. If thesolution “bubbles”, not much Grignard has formed yet. The aqueoussolution is extracted with a pipette of ether and the organic phase isdried over Na₂SO₄. A GC of the ethereal solution is recorded. When alarge amount of pyridine has formed compared to 2-bromopyridine,conversions are high. At −10° C., there has been little conversion.After warming up to room temperature and stirring for 1-2 hours, thereaction solution turns brown-yellow. A GC test shows completeconversion. Now the Grignard solution can be slowly added dropwise witha syringe pump to a solution of 1.748 g (11 mmol) ofdichloro-tert-butylphosphine in 10 ml of THF which has been cooled to−15° C. beforehand. It is important that thedichloro-tert-butylphosphine solution is cooled. At room temperature,considerable amounts of dipyridyl-tert-butylphosphine would be obtained.A clear yellow solution is initially formed, which then turns cloudy.The mixture is left to warm up to room temperature and to stirovernight. According to GC-MS, a large amount of product has formed. Thesolvent is removed under high vacuum and a whitish solid which is brownin places is obtained. The solid is suspended with 20 ml of heptane andthe solid is comminuted in an ultrasound bath. After allowing the whitesolid to settle out, the solution is decanted. The operation is repeatedtwice with 10-20 ml each time of heptane. After concentration of theheptane solution under high vacuum, it is distilled under reducedpressure. At 4.6 mbar, oil bath 120° C. and distillation temperature 98°C., the product can be distilled. 1.08 g of a colourless oil areobtained. (50%).

Analytical data: ¹H NMR (300 MHz, C₆D₆): δ 8.36 (m, 1H, Py), 7.67 (m,1H, Py), 7.03-6.93 (m, 1H, Py), 6.55-6.46 (m, 1H, Py), 1.07 (d, J=13.3Hz, 9H, t-Bu),

¹³C NMR (75 MHz, C₆D₆): δ 162.9, 162.6, 148.8, 135.5, 125.8, 125.7,122,8, 35.3, 34.8, 25.9 and 25.8.

³¹P NMR (121 MHz, C₆D₆) δ 97.9.

MS (El) m:z (relative intensity) 201 (M⁺, 2), 147 (32), 145 (100), 109(17), 78 (8), 57.1 (17).

Preparation of Ligand 1 (α,α′-bis(2-pyridyl(t-butyl)phosphino)o-xylene)

675 mg (27.8 mmol, 4 eq) of Mg powder are weighed out in a glovebox in a250 ml round-bottom flask with a nitrogen tap and magnetic stirrer bar,and the flask is sealed with a septum. High vacuum is applied to theround-bottom flask (about 5×10⁻² mbar) and it is heated to 90° C. for 45minutes. After cooling down to room temperature, 2 grains of iodine areadded and the mixture is dissolved in 20 ml of THF. The suspension isstirred for about 10 minutes until the yellow colour of the iodine hasdisappeared. After the magnesium powder has settled out, the cloudy THFsolution is decanted and the activated magnesium powder is washed twicewith 1-2 ml of THF. Then another 20 ml of fresh THF are added. At roomtemperature, a solution of 1.21 g (6.9 mmol) of α,α′-dichloro-o-xylenein 70 ml of THF is slowly added dropwise with a syringe pump. The THFsolution gradually turns a darker colour. The next day, the THFsuspension is filtered to remove the unconverted magnesium powder andthe content of Grignard compound is determined as follows:

1 ml of Grignard solution is quenched in a saturated aqueous solution ofNH₄Cl and extracted with ether. After drying over Na₂SO₄, a GC of theether solution is recorded. In qualitative terms, it is observed thatexclusively o-xylene has formed.

Quantitative Determination of the Content of the Grignard Solution:

1 ml of Grignard solution is quenched with 2 ml of 0.1 M HCl and theexcess acid is titrated with 0.1 M NaOH. A suitable indicator is anaqueous 0.04% bromocresol solution. The colour change goes from yellowto blue. 0.74 ml of 0.1 M NaOH has been consumed. 2 ml-0.74 ml=1.26 ml,corresponding to 0.126 mmol of Grignard compound. Since a di-Grignard ispresent, the Grignard solution is 0.063 M. This is a yield exceeding90%.

In a 250 ml three-neck flask with reflux condenser and magnetic stirrer,under argon, 1.8 g (8.66 mmol) of chlorophosphine (2-Py(tBu)PCl) aredissolved in 10 ml of THF and cooled to −60° C. Then 55 ml of theabove-stipulated Grignard solution (0.063 M, 3.46 mmol) are slowly addeddropwise at this temperature with a syringe pump. The solution at firstremains clear and then turns intense yellow. After 1.5 hours, thesolution turns cloudy. The mixture is left to warm up to roomtemperature overnight and a clear yellow solution is obtained. Tocomplete the reaction, the mixture is heated under reflux for 1 hour.After cooling, 1 ml of H₂O is added and the solution loses colour andturns milky white. After removing THF under high vacuum, a stringy, paleyellow solid is obtained. 10 ml of water and 10 ml of ether are addedthereto, and two homogeneous clear phases are obtained, which have goodseparability. The aqueous phase is extracted twice with ether. After theorganic phase has been dried with Na₂SO₄, the ether is removed underhigh vacuum and a stringy, almost colourless solid is obtained. Thelatter is dissolved in 5 ml of MeOH while heating on a water bath andfiltered through Celite. At −28° C., 772 mg of product are obtained inthe form of white crystals overnight. (51%). After concentration, it waspossible to isolate another 100 mg from the mother solution. The overallyield is 57.6%.

¹H NMR (300 MHz, C₆D₆): δ 8.58 (m, 2H, Py), 7.31-7.30 (m, 2H, benzene),7.30-7.22 (m, 2H, Py), 6.85-6.77 (m, 2H, Py), 6.73 (m, 2H, benzene),6.57-6.50 (m, 2H, py), 4.33 (dd, J=13.3 and 4.3 Hz, 2H, CH₂), 3.72-3.62(m, 2H, CH₂), 121 (d, J=11.8 Hz, 18H, tBu),

¹³C NMR (75 MHz, C₆D₆): δ 161.3, 161.1, 149.6, 137.8, 137.7, 134.5,133.3, 132.7, 131.4, 131,3, 125.7, 122,9, 30.7, 30,5, 28.2, 28,0, 26.5,26.4, 26.2, and 26.1.

³¹P NMR (121 MHz, C₆D₆) δ 8.8, EA calculated for C₂₆H₃₄N₂P₂: C, 71.54;H, 7.85; N, 6.56; P, 14.35, found: C, 71.21; H, 7.55; N, 6.56; P, 14.35.

Preparation of Methyl 3-methylbutanoate by Carbonylation of MethylTert-Butyl Ether (MTBE)

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (1.52 mg, 0.25 mol %), PTSA (14.3 mg, 3.75 mol %), 1 (8.7 mg,1 mol %) with a magnetic stirrer. Then toluene (2 ml) and MTBE (0.24 ml,2 mmol) are added under argon. This vial is placed in a metal platefabricated for the vial, and the plate with vial is transferred to a 300ml autoclave from Parr Instruments. The autoclave is purged three timeswith CO and then filled with 50 bar of CO at room temperature. Thereaction is carried out with magnetic stirring at 120° C. for 20 hours.The autoclave is subsequently cooled down to room temperature andcarefully let down. The yield was conducted using GC analysis withisooctane (200 μl) as internal standard (33% yield of methyl 3methylbutanoate).

This experiment shows that with the process of the invention it ispossible to react ethers directly by reaction of CO to give thecorresponding esters. Using the ligands employed in accordance with theinvention, significant yields are achieved in this reaction. Theinvention therefore makes it possible for ethers to be used in place ofethylenically unsaturated compounds as starting material for thepreparation of esters.

1. Process comprising the process steps of: a) initially charging anether having from 3 to 30 carbon atoms; b) adding a phosphine ligand anda compound comprising Pd, or adding a comprising Pd and a phosphineligand; c) feeding in CO; d) heating the reaction mixture, withconversion of the ether; wherein the phosphine ligand is a compound offormula (I)

where m and n are each independently 0 or 1; R¹, R², R³, R⁴ are eachindependently selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl; atleast one of the R¹, R², R³, R⁴ radicals is a —(C₃-C₂₀)-heteroarylradical; and R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl or—(C₃-C₂₀)-heteroaryl, may each independently be substituted by one ormore substituents selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —COO—(C₁-C₁₂)-alkyl,—COO—(C₃-C₁₂)-cycloalkyl, —CONH—(C₁-C₁₂)-alkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —CO—(C₁-C₁₂)-alkyl, —CO—(C₃-C₁₂)-cycloalkyl,—N—[(C₁-C₁₂)-alkyl]₂, —(C₆-C₂₀)-aryl, —(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl,—(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COOH, —SO₃H, —NH₂, halogen; andwherein no alcohol is added to the reaction mixture.
 2. Processaccording to claim 1, wherein the phosphine ligand is a compound of oneof the formulae (II) and (III)


3. Process according to claim 1, wherein at least two of the R¹, R², R³,R⁴ radicals are a —(C₃-C₂₀)-heteroaryl radical.
 4. Process according toclaim 1, wherein the R¹ and R³ radicals are each a —(C₃-C₂₀)-heteroarylradical.
 5. Process according to claim 1, wherein the R¹ and R³ radicalsare each a —(C₃-C₂₀)-heteroaryl radical; and R² and R⁴ are eachindependently selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl.
 6. Process according toclaim 1, wherein the R¹ and R³ radicals are each a —(C₃-C₂₀)-heteroarylradical; and R² and R⁴ are each independently selected from—(C₁-C₁₂)-alkyl.
 7. Process according to claim 1, wherein R¹, R², R³,R⁴, if they are a heteroaryl radical, are each independently selectedfrom furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, furazanyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, benzofuranyl, indolyl, isoindolyl,benzimidazolyl, quinolyl, isoquinolyl.
 8. Process according to claim 1,wherein the phosphine ligand is a compound of formula (1)


9. Process according to claim 1, wherein the ether in process step a) isa compound of formula (IV)

where R⁵ is selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₆-C₂₀)-aryl; R⁶ and R⁷ each independently are selected from —H,—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl; and R⁸ isselected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl. 10.Process according to claim 9, wherein R⁵ and R⁸ are each—(C₁-C₁₂)-alkyl.
 11. Process according to claim 9, wherein R⁶ and R⁷each independently are selected from —H, —(C₁-C₁₂)-alkyl,—(C₆-C₂₀)-aryl.
 12. Process according to claim 9, wherein not more thanone of the radicals R⁶ and R⁷ is —H.
 13. Process according to claim 1,wherein the compound comprising Pd in process step b) is selected frompalladium dichloride, palladium(II) acetylacetonate, palladium(II)acetate, dichloro(1,5-cyclooctadiene)palladium(II),bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II), palladium(cinnamyl) dichloride.